A mouse model for the cystic fibrosis ΔF508 mutation

Most cystic fibrosis (CF) patients produce a mutant form (ΔF508) of the cystic fibrosis transmembrane conductance regulator (CFTR), which is not properly processed in normal cells but is active as a chloride channel in several experimental systems. We used a double homologous recombination ('Hit and Run') procedure to generate a mouse model for the ΔF508 mutation. Targeted embryonic stem (ES) cells (Hit clones) were found; of these either 80 or 20% of the clones had lost the ΔF508 mutation, depending on the distance between the linearization site in the targeting construct and the ΔF508 mutation. Correctly targeted clones underwent a second selection step resulting in ES cell clones (Run clones) heterozygous for the ΔF508 mutation with an efficiency of 2-7%. Chimeric mice were generated and offspring homozygous for the ΔF508 mutation showed electrophysiological abnormalities in nasal epithelium, gallbladder and in the intestine, and histological abnormalities in the intestine, typical of CF. Our data suggest that the ΔF508 mice have residual ΔF508 CFTR activity which would explain the mild pathology of the ΔF508 mice. The ΔF508 mouse may provide a useful model for the study of the processing defect of ΔF508 CFTR and for the development of novel therapeutic approaches based on circumvention of the processing block.